The effects of polyvinyl alcohol-coated selenium nanoparticles on memory impairment in rats

Abstract

Some mineral elements exert beneficial neuroprotection, especially in the form of nanoparticles. The aim of the present study was to evaluate the effects of selenium nanoparticles (SeNPs) and polyvinyl alcohol (PVA)-coated SeNPs (PVA-SeNPs) on Alzheimer’s disease (AD) in a rat model of AD. Twenty-eight rats were randomly divided into four groups of seven rats: control, Alz, Alz + Se, and Alz + Se-PV groups. PVA-SeNPs and SeNPs were chemically synthesized and orally administrated (0.4 mg/kg) to the AD rats for one month. AD was induced by an intracerebroventricular (ICV) injection of streptozotocin (STZ). The memory function was assessed by the novel object recognition (NOR) and passive avoidance learning (PAL) tests. The expression of hippocampal brain-derived neurotrophic factor (BDNF) and stress oxidative markers (MDA and TAC), and the number of amyloid-beta (Aβ) plaques were assessed using ELISA kits, biochemical methods, and Congo red staining, respectively. The results of the behavioral tests showed that the discrimination index in the NOR test increased in the Alz + PVA-SeNPs group compared to the Alz group. Memory performance in the PAL task improved in the PVA-SeNPs and SeNPs groups compared to the Alz group. The level of the BDNF in both of the Alz treatment groups (PVA-SeNPs and SeNPs) showed a significant increase compared to the Alz group. MDA levels and Aβ plaques decreased in both NPs-treated Alz groups, while TAC levels decreased in all Alz groups. PVA-SeNPs were more effective than SeNPs in the improvement of the cognition deficit. The results suggest that PVA-SeNPs improve the cognition and memory deficit induced by an ICV injection of STZ through a decrease in the number of Aβ plaques and malondialdehyde levels and an increase in the BDNF levels.

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Vol.:(0123456789)
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Metabolic Brain Disease
https://doi.org/10.1007/s11011-022-01084-4
ORIGINAL ARTICLE
The effects ofpolyvinyl alcohol‑coated selenium nanoparticles
onmemory impairment inrats
NasrinHashemi‑Firouzi1· SiminAfshar1· SaraSoleimaniAsl2· AlirezaSamzadeh‑Kermani3·
BaharehGholamigeravand2· KimiaAmiri4· MahsaMajidi4· SiamakShahidi1
Received: 23 October 2021 / Accepted: 13 September 2022
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
Some mineral elements exert beneficial neuroprotection, especially in the form of nanoparticles. The aim of the present
study was to evaluate the effects of selenium nanoparticles (SeNPs) and polyvinyl alcohol (PVA)-coated SeNPs (PVA-
SeNPs) on Alzheimer’s disease (AD) in a rat model of AD. Twenty-eight rats were randomly divided into four groups of
seven rats: control, Alz, Alz + Se, and Alz + Se-PV groups. PVA-SeNPs and SeNPs were chemically synthesized and orally
administrated (0.4mg/kg) to the AD rats for one month. AD was induced by an intracerebroventricular (ICV) injection of
streptozotocin (STZ). The memory function was assessed by the novel object recognition (NOR) and passive avoidance
learning (PAL) tests. The expression of hippocampal brain-derived neurotrophic factor (BDNF) and stress oxidative markers
(MDA and TAC), and the number of amyloid-beta (Aβ) plaques were assessed using ELISA kits, biochemical methods, and
Congo red staining, respectively. The results of the behavioral tests showed that the discrimination index in the NOR test
increased in the Alz + PVA-SeNPs group compared to the Alz group. Memory performance in the PAL task improved in
the PVA-SeNPs and SeNPs groups compared to the Alz group. The level of the BDNF in both of the Alz treatment groups
(PVA-SeNPs and SeNPs) showed a significant increase compared to the Alz group. MDA levels and Aβ plaques decreased
in both NPs-treated Alz groups, while TAC levels decreased in all Alz groups. PVA-SeNPs were more effective than SeNPs
in the improvement of the cognition deficit. The results suggest that PVA-SeNPs improve the cognition and memory deficit
induced by an ICV injection of STZ through a decrease in the number of Aβ plaques and malondialdehyde levels and an
increase in the BDNF levels.
Keywords Alzheimer’s disease· Memory· Rat· Selenium nanoparticles· Polyvinyl alcohol
Introduction
Selenium (Se) is a trace element (micronutrient) that plays
a role in body functions (Avery and Hoffmann 2018). Se
supplementation is effective for human health (Rayman
2012). Se exerts antioxidant, anti-apoptotic, and anti-
inflammatory effects (Qian etal. 2019; Wang etal. 2017).
However, the dose, duration, and form of intervention are
still controversial (Köhrle 2015). The nanoparticles (NPs)
have recently attracted researchers’ attention (Schubert
and Chanana 2019). They have different physicochemical
properties. On the other hand, NPs, including selenium
nanoparticles (SeNPs) increase the efficacy of the element
used in the NPs (Solovyev etal. 2018). Se is a toxic ele-
ment in many species (Maiyo and Singh 2017). SeNPs are
less toxic than inorganic and organic forms of Se (Schubert
and Chanana 2019).
NPs can be used as therapeutic agents for neurodegen-
erative diseases, specifically Alzheimer’s disease (AD) and
Parkinson’s disease (Padmanabhan etal. 2020). AD is char-
acterized by progressive memory and cognitive loss (Silva
etal. 2021). The accumulation of amyloid-β (Aβ) plaques,
* Siamak Shahidi
shahidi@umsha.ac.ir; siamakshahidi@yahoo.com
1 Neurophysiology Research Center, Hamadan University
ofMedical Sciences, Hamadan, Iran
2 Department ofAnatomy, School ofMedicine, Hamadan
University ofMedical Sciences, Hamadan, Iran
3 Department ofChemistry, Faculty ofScience, University
ofZabol, Zabol, Iran
4 School ofMedicine, Hamadan University ofMedical
Sciences, Hamadan, Iran

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oxidative stress, inflammation, neuronal apoptosis, and
synaptic dysfunction play a role in the development of AD
(Cheignon etal. 2018; Jokar etal. 2019; Komaki etal. 2019;
Tönnies and Trushina 2017). The currently used drugs are
not very effective in the treatment of AD (Cao etal. 2018).
Drug delivery through the blood-brain barrier is a complex
process and there is a need for nanosized particles for drug
delivery in the nervous system.
Coating of the NPs increases their stability. The water-
soluble synthetic polymer is used in cosmetics and in sev-
eral medical applications, such as cartilage replacements and
contact lenses (Baker etal. 2012; Burnett 2017; Tang etal.
2012). There are stabilized NPs with various ligands that are
produced in coated form, such as polyvinyl alcohol (PVA).
PVA is used as a capping agent in the synthesis of various
NPs, such as silver nanoparticles (Triyana etal. 2017), gold
nanoparticles (Ma etal. 2019), and iron nanoparticles (Rah-
ayu etal. 2018).
PVA stabilizes the SeNPs (Shah etal. 2007) and is a low-
cost and non-hazardous organic polymer with good water
solubility (Hmar 2018). PVA is diffused in the NPs, prevents
their accumulation for a longer duration, and increases the
stability of NPs. Coating of SeNPs with PVA is done due to
advantages, such as making it non-toxic, increasing circula-
tion time and drug loading, and various other potential func-
tions (Badr and Mahmoud 2006). More effectiveness of the
PVA-coated rivastigmine microspheres has been reported
for the treatment of AD (Gao etal. 2021).
SeNPs can be potential therapeutic agents for the treat-
ment of AD (Duntas and Benvenga 2015; Nazıroğlu etal.
2017; Yin etal. 2015). SeNPs have antioxidants and anti-
aggregative properties and alleviate typical aspects of neu-
rodegenerative diseases more effectively than Se (Rajeshku-
mar etal. 2019; Tang etal. 2021; Zhai etal. 2017). Oxidative
stress declines the activity of brain-derived neurotrophic fac-
tor (BDNF). BDNF is one of the neurotrophic factors, which
is extremely important for brain development and maintains
neuronal growth and development and synaptic functions
(Gao etal. 2022). BDNF protects neurons from toxic dam-
age and increases the survival of neurons in AD.
Se is a neuroprotective agent against BDNF reduction
and oxidative stress in the brain (Abedelhaffez and Hassan
2013) and SeNPs reverse Streptozotocin-induced neurotox-
icity (Gholamigeravand etal. 2021). Chitosan-coated SeNPs
enhance the efficiency of transplanted stem cells (Soleimani
Asl etal. 2021). It seems that PVA-coated SeNPs (PVA-
SeNPs) could alleviate oxidative stress and memory impair-
ment due to STZ neurotoxicity. Therefore, the aim of the
present study was to evaluate the effects of PVA-SeNPs in
a rat model of AD.
Materials andmethods
Animals
Twenty-eight male Wistar rats (250 ± 50g) were housed
under standard conditions (12 h light/dark cycle at
23 ± 2°C). The Medical Ethics Committee of Hamadan
University of Medical Sciences approved all treatment and
experimental procedures (IR.UMSHA.REC.1398.629) and
they were performed in accordance with the National Insti-
tutes of Health Guide for Care and Use of Laboratory Ani-
mals (NIH Publication No. 85–23, revised 1985).
Drugs
Ketamine and Xylazine were purchased from Alfasan, Hol-
land. Streptozotocin (STZ) was purchased from Santa Cruz
Biotechnology, USA, and was dissolved in 0.9% saline.
and sodium sulfite were purchased from Merck Company,
Germany.
Preparation ofPVA‑SeNPs
There are several methods for the synthesis of SeNPs,
but chemical deposition is a simple method with higher
efficiency than others. Se powder was used as the start-
ing material, not as Se salt. Therefore, there was no need
for a reducing agent to obtain neutral metallic SeNPs.
Se powder was dissolved in sodium sulfite to convert to
the sodium selenosulphate clear solution. Then, glacial
acetic acid was added slowly and dropwise to the solu-
tion along with warming and vigorous stirring in order
to attain SeNPs.
There are many reports in the literature on the use of
polymers and biopolymers as stabilizing nanosized parti-
cles. In this work, PVA was used as a stabilizer by coating
on SeNPS and there is no difference between the sizes of
NPs alone and in combination with PVA. PVA only causes
a delay in the aggregation of NPs, which can be extended by
reducing the temperature and keeping in dark.
Characterization ofPVA‑SeNPs
The surface morphology, structure, and elemental composi-
tion of PVA-SeNPs were characterized by scanning electron
microscopy (SEM) (Hitachi S4160), energy dispersive X-ray
analysis (EDAX), and Fourier-transform infrared spectros-
copy (FTIR).

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Induction ofAD model
The surgical procedure was performed as in previous stud-
ies (Afshar and Shahidi 2018; Shahidi etal. 2019). In brief,
the rats were anesthetized with a mixture of xylazine and
ketamine (10 / 100mg/kg), and then, the animals were
transferred to a stereotaxic apparatus (Stoelting, USA). One
unilateral cannula was implanted for intracerebroventricular
(ICV) injection of STZ according to the following stereotaxic
coordinates: AP: −0.9mm from bregma; ML: +1.5mm from
the midline, and DV: −2.2mm from the skull surface (Paxi-
nos and Watson 1998). The dental cement held the ICV can-
nula. Animals were allowed to recover for one week. The
STZ solution (3mg/kg, 10μL on each side) was bilaterally
injected into the ICV on days one and three post-treatment.
Experimental groups
Twenty-eight rats were randomly divided into four groups
of seven rats:
1- Control rats did not receive any treatment or surgery.
2- Alz group: The animals received an ICV injection of
STZ and were treated with a vehicle for one month after
STZ administration.
3- Alz + Se group: The animals received an ICV injection
of STZ, and then were treated orally with (0.4mg/kg) for
one month (Abdulmalek and Balbaa 2019; Al-Kahtani
and Morsy 2019).
4- Alz + Se-PVA group: the ICV received an ICV injection
of STZ and then were treated orally with PVA-SeNPs
(0.4mg/kg) for one month (Abdulmalek and Balbaa
2019; Al-Kahtani and Morsy 2019).
Behavioral assessments
Novel object recognition test
The apparatus of the novel object recognition (NOR) test
is a square open box (35 × 43 × 40cm), which is made of
dark brown wooden. The habituation was performed in the
empty box for 5min. After two hours, a learning trial was
done using two similar kinds of objects (familiar) (~ 8.5cm
height × 7cm length × 3.5cm width) for 5min. The test
trial was performed 24hours later. In the test trial, one of the
familiar objects and a novel object were presented to each rat
for 5min. A video camera recorded the time spent in prox-
imity to each object for 5min. The exploration behaviors,
including orienting toward the object, sniffing, or placing
the nose within 1cm of the object were also recorded. The
discrimination index (DI) was calculated as follows: Time
exploring the novel object divided by the total exploration
time (Almasi etal. 2018; Beigi etal. 2018). The box and
objects were cleaned with 50% ethanol to remove any resid-
ual odors after each session.
Passive avoidance learning test
Passive avoidance learning was evaluated by the passive
avoidance learning (PAL) test (30cm × 20cm × 20cm). The
apparatus has two dark and light compartments separated
by a guillotine door (8cm × 6cm). In the learning trial, the
rat was placed in the light compartment and the guillotine
door was raised. The rat was allowed to enter the dark room
and received an electric shock (50Hz, 0.2mA) for 0.5s.
After 24h, the retention trial was conducted for the memory
test with no shock delivery. The step-through latency in the
retention trial (STLr) (Hasanein and Shahidi 2012) and the
average time spent in the dark compartment (TDC) were
measured (Shahidi etal. 2017).
Oxidative stress assessments
After the last day of the behavioral tests, the animals were
anesthetized, sacrificed, and the hippocampal tissues were
removed. Total antioxidant capacity (TAC) and the malon-
dialdehyde (MDA) levels in brain tissue were determined
according to the previous protocols (Afshar etal. 2019).
BDNF measurement
The brains were removed after anesthesia. The hippocampus
was homogenized in phosphate saline buffer and a 1% cock-
tail of protease inhibitors. After centrifugation, supernatants
were stored at −80°C until measurement of BDNF levels
with a commercial ELISA kit (ZellBio, Germany). The
procedure was performed according to the manufacturer’s
instructions. All samples and standards were made using
blocking and sample buffer. The BDNF peak absorption was
determined at 450nm.
Histological assessments
The serial sections of the brain were dehydrated, cleaned,
and stained according to the following protocol: 1) Sections
were incubated with an alkaline solution of Congo red for
10min; 2) Congo red solution was replaced with NaOH
solution in distilled water for 5min; 3) Sections were washed
in distilled water for 5min.; 4) Stained with hematoxylin
solution for 3min; 5) Washed in distilled water for 10; and
6) dehydrated in ethanol, cleared in xylene, and mounted.
The amyloid plaques were measured using ×400 magnifica-
tion (Olympus, Japan).

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Statistical analysis
The one-way ANOVA determined the statistically signifi-
cant differences between the experimental groups, followed
by the post hoc Tukey test. All results are presented as
mean ± SEM. A P- value <0.05 was considered significant
in all cases.
Results
Results ofmorphology ofnanoparticles formulation
SEM results
The morphology and the size of SeNPs were studied by
SEM. Figure1A shows the SEM images obtained from the
Se surface and coating NPs with PVA did not change their
size. The SEM images of SeNPs were found with a spherical
and uniform structure. The uncoated SeNPs were compact
in the absence of PVA.
X‑ray diffraction results
Figure1B displays that the X-ray diffraction pattern of the
SeNPs coated with PVA at an angle of 3θ was between 0°
and 80°. Obtained patterns revealed the well-known diffrac-
tion peaks of PEO at 3θ. It was clear that the addition of
PVA to SeNPs increased the intensity of the SeNPs peaks,
indicating an increase in the crystalline phase.
EDAX results
EDAX elemental analysis confirmed the composition of syn-
thesized SeNPs. The observed spectrum of SeNPs proved
the presence of only pure SeNPs. The EDAX spectrum of
the nanocomposite is shown in Fig.1C.
FTIR
Figure1D shows FTIR spectra of SeNPs. SeNPs were ana-
lyzed by an FTIR spectrometer (Broker Optics Ft Tensorr
27, Germany). The spectral range was 400 to 4000 (cm−1).
The spectra showed no absorption related to the binding
of Se with oxygen, which indicated the formation of nano-
selenium oxide.
NOR test results
Figure2 illustrates the DI values in the NOR test. The one-
way ANOVA results indicated a significant difference in DI
between groups (F (3, 27) =8.811, P < 0.001). The control
Fig. 1 Determination of selenium nanoparticles by Transmission Electron Microscopy (A), X-ray powder diffraction (B), energy dispersive
X-ray spectroscopy (C) and fourier-transform infrared spectroscopy technique (D)

Metabolic Brain Disease
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group was found with a significant increase in DI compared
to the Alz and Alz + Se groups (p < 0.001 and p < 0.01, per-
ceptively). The Alz + Se + PVA group also exhibited a sig-
nificant increase in DI compared to the Alz group (p < 0.05).
PAL test results
The one-way ANOVA results showed no significant dif-
ference between groups in the step-through latency in the
learning trial (F (3, 27) =2.04, p = 0.135 > 0.05). The signifi-
cant difference in STLr was confirmed by one-way ANOVA
(F (3, 27) = 4.54, P < 0.001; Fig.3A). Tukey’s test results
showed a significant decrease in STLr Alz rats on test day
compared to the control (p < 0.001), Alz + Se (p < 0.01), and
Alz + Se + PVA (p < 0.01) groups. No significant difference
was found between the Alz + Se and Alz + Se + PVA groups.
In addition, there was a significant difference in TDC
between groups (F (3, 27) =10.991, p < 0.001; Fig.3B).
The Tukey’s test results showed that the Alz group spent
more time in the dark compartment of the apparatus com-
pared to the control, Alz + Se, and Alz + Se + PVA groups
(P < 0.001).
Measurement ofoxidative stress parameters
Figure4A displays the hippocampal TAC levels in groups.
A significant difference was identified in the levels of TAC
between the groups evidenced by one-way ANOVA results
(F (3, 15) = 24.053, P < 0.001). The TAC levels signifi-
cantly decreased in the Alz group compared to the control
group (P < 0.001). In the Alz animals treated with Se and
Se + PVA, the TAC levels significantly decreased compared
to the control group (P < 0.01 and P < 0.001, respectively).
The TAC levels decreased in the Alz + Se + PVA group com-
pared to the Alz + Se group (P < 0.05).
A one-way ANOVA results demonstrated significant dif-
ferences in the levels of hippocampal MDA, as a biomarker
of lipid peroxidation, between groups [F (3, 15) =172.30,
P < 0.001). As shown in Fig.4B, the MDA levels in the hip-
pocampus of the Alz group significantly increased compared
to the control group (P < 0.001). Compared with the Alz
group, MDA levels significantly decreased in the Alz + Se
and Alz + Se + PVA groups (P < 0.001). There were no sig-
nificant differences in the MDA levels between the control,
Alz + Se, and Alz + Se + PVA groups.
Measurement ofBDNF
The one-way ANOVA results showed a statistically sig-
nificant difference in the levels of BDNF protein between
the groups (F (3, 15) = 31.331, P < 0.001) (Fig. 5). Tuk-
ey’s test results showed that in the Alz group, the levels of
BDNF significantly reduced compared to the control group
(P < 0.001). BDNF levels were higher in the Alz + Se and
Alz + Se + PVA groups than in the Alz group (P < 0.05). The
levels of BDNF in control rats were significantly higher than
in the Alz + Se and Se + PVA groups (P < 0.001).
Congo red staining results
Congo red staining assessed the Aβ plaques in the cortex
of the animals (Fig.6A). Congo red binds to the insoluble
Aβ plaques with a high affinity and red spots exhibit as Aβ
plaques. The one-way ANOVA results indicated signifi-
cant differences in the number of Aβ plaques between the
groups (F (3, 15) = 22.341, P < 0.001; Fig.6B). The Alz rats
were found with a significant increase in the number of Aβ
Fig. 2 Comparison of discrimi-
nation index results of novel
object recognition test between
experimental groups: control
group, Alz group received icv
streptozotocin+vehicle, Alz + Se
group received icv injection
of streptozotocin+selenium
nanoparticles, Alz + Se + Pv
group received icv- streptozo-
tocin + polyvinyl alcohol coated
selenium nanoparticles. Data
are shown as mean ± S.E.M.
##P< 0.01 and ###P< 0.001
as compared with the control
group.!P< 0.05 as compared
with the Alz group
### ##
!
0
10
20
30
40
50
60
70
80
90
ControlAlz Alz+Se Alz+Se +Pv
Discrimination Index %
Group

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plaques compared to the control rats (P < 0.001). The num-
ber of Aβ plaques in the Azl + Se and Alz + Se + PVA rats
was significantly lower than in Alz rats (P < 0.05).
Discussion
In the current study, SeNPs were coated with PVA using
a chemical method. The use of PVA as a capping agent
will make the agglomeration of metal nanoparticles longer
by intercalation of polymer molecules between them and
chemical interactions of NPs with hydroxyl polar func-
tional groups of PVA. These two types of NPs are not
different in shape and size. PVA is diffused in the NPs.
The effect of oral treatment of with PVA-SeNPs was evalu-
ated on the STZ- induced AD. We investigated the effects
of PVA-SeNPs treatment against memory impairment
in ICV-STZ injected rats. The results showed the effec-
tiveness of Se coated with PVA in learning and memory
improvement. PVA-SeNPs treatment improved memory
impairment caused by STZ through increasing antioxidant
capacity.
The ICV administration of STZ is a useful approach
to inducing AD-like sporadic dementia in animals (Grieb
2016; Kamat etal. 2016). The ICV administration of STZ
can cause severe memory impairment and the accumula-
tion of Aβ plaques associated with increased oxidative
stress (Pathan etal. 2006). Our results showed cognition and
memory impairment in the ICV-STZ injected rats. Memory
impairment in the STZ- treated rats was associated with a
decrease in the total triglycefides levels and an increase in
the MDA concentration.
Fig. 3 Comparison of step-
through latency in the retention
trial (STLr) (a) time spent in the
dark compartment (TDC) (b) of
the passive avoidance learn-
ing test between experimental
groups: control group, Alz
group received icv strepto-
zotocin +vehicle, Alz + Se
group received icv injection
of streptozotocin+selenium
nanoparticles, Alz + Se + Pv
group received icv- strepto-
zotocin+ polyvinyl alcohol
coated selenium nanoparticles.
###P< 0.001 as compared with
the control group.!!P< 0.01 and
!!!P< 0.001 as compared with
the Alz group
###
!! !!
0
50
100
150
200
250
300
ControlAlz Alz+Se Alz+Se +Pv
STLr (sec)
Group
A
###
!!!
!!!
0
50
100
150
200
250
ControlAlz Alz+Se Alz+Se +Pv
TDC (sec)
Group
B

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ICV-STZ injected rats showed the formation of Aβ
plaques in the brain (Chen etal. 2013), which confirms
our results. The present study demonstrated that the ICV
injection of STZ caused a decrease in the hippocampal
BDNF levels. BDNF is an important neurotrophin, and
its expression and concentration are reduced in postmor-
tem brain samples of AD (Du etal. 2018; Nunes etal.
2018). Reduced BDNF levels are associated with cogni-
tive impairment (Nunes etal. 2018). In addition, Aβ is
involved in the inhibition of BDNF expression (Rajasekar
etal. 2017; Zheng etal. 2010) and the accumulation of
soluble Aβ oligomers increased BDNF deficiency (Witty
etal. 2013). Accumulation of Aβ in the brain is associated
with memory decline.
The results of our study showed that the administration of
SeNPs improved STZ-induced memory deficits in the NOR
and PAL tests. Similarly, Se showed the protective effects
on scopolamine-induced memory impairment in aged rats
(Balaban etal. 2017). Se is a non-metal element, which is
involved in cell cycle progression (Srivastava etal. 2014).
SeNPs have lower toxicity than Se (Avery and Hoffmann
2018).
It is reported that methionine-coated SeNPs promoted
hippocampal neurogenesis in a mouse model of AD (Zheng
etal. 2017). Current data showed that treatment of STZ-
injected rats with PVA-SeNPs improved memory deficits
and reduced Aβ plaques in the brain. Our finding is in line
with other studies, in which SeNPs stabilized with chitosan
Fig. 4 Changes in TAC (A), and
MDA (B) levels in brain tissues
of rats between experimental
groups: control group, Alz
group received icv strepto-
zotocin + vehicle, Alz + Se
group received icv injection
of streptozotocin+selenium
nanoparticles, Alz + Se + Pv
group received icv- streptozo-
tocin +polyvinyl alcohol coated
selenium nanoparticles. MDA
(malondialdehyde) and TAC
(total antioxidant capacity).
##P< 0.01 and ###P< 0.001
as compared with the control
group. !!!P< 0.001 as compared
with the Alz group. $P< 0.05
as compared with the Alz + Se
group
### ##
###
$
0
0.04
0.08
0.12
0.16
0.2
ControlAlz Alz+Se Alz+Se +Pv
TAC (µmol/mg protein)
Group
A
###
!!! !!!
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
ControlAlz Alz+Se Alz+Se +Pv
MDA (µmol/mg protein)
Group
B

Metabolic Brain Disease
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inhibited Aβ fibril formation invitro (Vicente-Zurdo etal.
2020) and reduced Aβ aggregation (Yang etal. 2018).
Se is a metallic antioxidant and essential micronutrient.
In addition, nano-selenium is able to improve biological
activities and bioavailability. SeNPs protect against oxida-
tive stress and are widely used for the treatment of various
neurological diseases. SeNPs have antimicrobial and anti-
oxidant properties (Boroumand etal. 2019). PVA-SeNPs
showed more effectiveness than SeNPs as both have almost
similar biological activity. The coated SeNPs present higher
biocompatibility than SeNPs (Badr and Mahmoud 2006;
Nadeem etal. 2016). PVA is a stabilizer to control the mor-
phology of NPs (Burnett 2017; Pencheva etal. 2012). In the
current study, SeNPs were stabilized with PVA.
PVA is a non-toxic, biocompatible, and chemically stable
compound for biomedicine application (Baker etal. 2012).
SeNPs exhibit lower cytotoxicity (Tran etal. 2016). The NPs
have low toxicity and PVA-SeNPs exhibited lower toxicity
than SeNPs on fibroblast cells (Boroumand etal. 2019). It
has been shown that the coated SeNPs present higher circu-
lation time and drug loading than SeNPs. PVA used for the
synthesis of SeNPs improved cognition and memory ability
of the SeNPs for the treatment of AD by increasing BDNF
levels and reducing Aβ plaques. PVA-SeNPs and SeNPs
have low toxicity on fibroblast cells and have antibacterial
activity (Boroumand etal. 2019).
Both PVA-SeNPs and SeNPs decreased the MDA levels;
however, they did not affect the TAC levels. Similarly, other
studies have reported that NPs do not act as anti-oxidant
agents (D'Angelo etal. 2009). In a recent study, treatment of
rats receiving STZ with SeNPs, improved memory impair-
ment and decreased the Aβ plaques through increasing anti-
oxidant capacity (Gholamigeravand etal. 2021). Oxidative
stress is a factor involved in the development of AD by pro-
moting the synthesis and deposition of Aβ plaques (Chauhan
and Chauhan 2006). BDNF, an important neurotrophin pro-
tein in plasticity and synaptic growth, is involved in the pro-
gression of AD (Tanila 2017). Both PVA-SeNPs and SeNPs
increase the levels of BDNF and decrease the Aβ plaques,
which is consistent with the results of the study reporting
that NPs are involved in neuroprotection and the signaling
pathway of BDNF (D'Angelo etal. 2009). A decrease in the
deposition of Aβ increased the BDNF levels (Zhang etal.
2012), and learning and memory were improved by BDNF
(Fahnestock 2011).
There were no significant differences between the
PVA-SeNPs - and SeNPs-treated AD rats in the number
of plaques, MDA levels, and staying in the dark compart-
ment in the PAL test in treated groups. Only one signifi-
cant difference was observed in the NOR test. PVA-SeNPs
improved memory impairment more effectively than
SeNPs. It seems that coating with PVA provided increased
biological activity; however, more experiments should be
conducted in the future to explain this. Further studies in
the future are suggested to clarify the detailed mechanisms
of PVA-SeNPs on AD. In conclusion, the present study
demonstrated that the oral administration of PVA-SeNPs
increased BDNF levels, reduced Aβ plaques deposition,
and improved cognition and memory deficit induced by
ICV-STZ.
Fig. 5 comparison of the
hippocampal brain-derived
neurotrophic factor (BDNF)
protein between the experi-
mental groups: control
group, Alz group received
icv streptozotocin+vehicle,
Alz + Se group received icv
injection of streptozotocin+
selenium nanoparticles,
Alz + Se + Pv group received
icv- streptozotocin + polyvi-
nyl alcohol coated selenium
nanoparticles. ###P< 0.001
as compared with the control
group.!P< 0.05 as compared
with the Alz group
###
###
!###
!
0
10
20
30
40
50
60
70
80
Control Alz Alz+Se Alz+Se +Pv
BDNF (ng/mg protein)
Group

Metabolic Brain Disease
1 3
Author contribution Conceptualization: Nasrin Hashemi-Firouzi,
Simin Afshar, Sara Soleimani Asl, Siamak Shahidi; Data curation:
Simin Afshar, Alireza Samzadeh-Kermani, Bahareh Gholamigeravand,
Kimia Amiri, Mahsa Majidi; Formal analysis: Nasrin Hashemi-Firouzi,
Sara Soleimani Asl, Siamak Shahidi; Funding acquisition: Siamak
Shahidi; Investigation: Nasrin Hashemi-Firouzi, Simin Afshar, Sara
Soleimani Asl, Siamak Shahidi; Methodology: Nasrin Hashemi-Fir-
ouzi, Simin Afshar, Sara Soleimani Asl, Alireza Samzadeh-Kermani,
Siamak Shahidi; Project administration: Siamak Shahidi; Software:
Sara Soleimani Asl; Supervision: Siamak Shahidi; Visualization:
Simin Afshar, Sara Soleimani Asl, Alireza Samzadeh-Kermani, Siamak
Shahidi; Writing - original draft; Writing - review & editing: Nasrin
Hashemi-Firouzi, Sara Soleimani Asl, Siamak Shahidi.
Funding This research was supported by a grant (No. 9808286340)
from the Neurophysiology Research Center of the Hamadan Univer-
sityof Medical Sciences.
Data availability Data cannot be available for reasons disclosed in the
data availability statement.
Code availability Not applicable.
Declarations
Ethics approval The Medical Ethics Committee of Hamadan Uni-
versity of Medical Sciences (IR.UMSHA.REC.1398.629) approved
all treatment and experimental procedures of the current study. All
research and animal care procedures were in accordance with the
National Institutes of Health Guide for Care and Use of Laboratory
Animals (Publication No. 85–23, revised 1985).
Consent to participate Not applicable.
Consent for publication All author agree for publication.
Fig. 6 Light micrographs
of cortical amyloid plaques.
(A) Sections derived from a,
control; b, Alz; c, Alz + Se
and d, Alz + Se + Pv groups
stained by Congo red. The red
arrow shows amyloid plaques.
Magnification × 400. (B)
The mean number of amyloid
plaques among the experimen-
tal groups: control group, Alz
group received icv strepto-
zotocin +vehicle, Alz + Se
group received icv injection
of streptozotocin+ selenium
nanoparticles, Alz + Se + Pv
group received icv- strepto-
zotocin + polyvinyl alcohol
coated selenium nanoparticles.
###P< 0.001 as compared with
the control group. !P< 0.05 as
compared with the Alz group
###
###
!
###
!
0
2
4
6
8
10
12
ControlAlz Alz+Se Alz+Se +Pv
Number of amyloid plaques
Group
B

Metabolic Brain Disease
1 3
Conflict of interest There are no conflicts of interest to declare.
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